DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2 Applicant's amendment, filed on 01/17/2024, is acknowledged.
3. Claims 11-16, 24-28, 75-80 and 87-89 are pending and under examination.
4. Applicant’s IDS, filed 09/19/2023, is acknowledged.
5. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
6. Claims 11-13, 15, 75-77 and 87-89 are rejected under 35 U.S.C. 103 as being unpatentable over Furie et al. (Arthritis Rheumatol. 69(2):376-386, 2017) in view of Yin et al (The Journal of Immunology, 2002, 169: 2148–2155), as is evidenced by US 20220340669.
Furie et al anifrolumab (comprising the claimed sequences) substantially reduced disease activity compared with placebo across multiple clinical end points in the patients with moderate- to-severe SLE (see abstract) via preventing signaling by all type I IFNs. Furie et al teach that patients receive intravenous anifrolumab (300 mg or 1,000 mg), every 4 weeks (Q4W) for 48 weeks (Abstract-methods). Furie et al teach that the primary end point was analyzed in the modified intent-to-treat (TT) population with high IFN gen signature at screening (IFN-high subpopulation) (page 378, right col., 3 4). The median neutralization ratios of a 21- gene type I IFN signature in the IFN-high subpopulation at week 24 were 89.7 and 91.7 for the anifrolumab 300-mg and anifrolumab 1,000-mg groups, respectively (page 383, right col, top ¶). Furie et al teaches that the IFN-high subgroup represents a subpopulation more likely to benefit from the addition of anifrolumab to standard therapy (p. 385, right col., 1st ¶). Furie et al teach that patients (n = 305) were randomized to receive intravenous anifrolumab (300 mg or 1,000 mg) or placebo, in addition to standard therapy, every 4 weeks for 48 weeks. Randomization was stratified by SLE Disease Activity Index 2000 score (<10 or ≥10), oral corticosteroid dosage (<10 or ≥10 mg/day), and type I IFN gene signature test status (high or low) based on a 4-gene expression assay (see Methods). IFN gene signature was determined at a central laboratory using an analytically validated 4-gene (IFI27, IFI44, IFI44L, and RSAD2) quantitative polymerase chain reaction (PCR)–based test from patients’ whole blood. A predetermined, ΔCt-based cutoff point, in the trough of the bimodal distribution, was used to segregate patients with a high IFN gene signature from patients with a low IFN gene signature at baseline (see Study design). Furie et al teach that the primary end point was analyzed in the modified intent-to-treat (ITT) population (all randomized patients who received any dose of study drug and had baseline primary efficacy measurements) and a modified ITT subpopulation of patients with a high IFN gene signature at screening (IFN-high subpopulation). The study result was considered positive if the primary end point was met in either of the 2 study populations (see Statistical analysis and Tables 1-2 and Fig. 1).
Claim 89 is included because anifrolumab comprises an Fc region having L234F mutation as is evidenced by US 20220340669 that anifrolumab is a modified IgG class monoclonal antibody specific for IFNAR1 comprising in the Fc region an amino acid substitution of L234F, L235E and/or P331S, as numbered by the EU index as set forth in Kabat [0171].
The reference teachings differ from the claimed invention only in the recitation that the subject has an IL-10 plasma concentration lower than about 2 pg/ml at baseline in claims 11 and 87.
Yin et al teach that low levels of IL-10 are associated with active SLE. In particular, Yin et al teach the role of IL-10 in the regulation of murine lupus, IL-10 gene-deficient (IL-10-/-) MRL-Faslpr (MRL-Faslpr IL-10-/-) mice (i.e., lower than about 2 pg/ml) were generated and their disease phenotype was compared with littermates with one or two copies of an intact IL-10 locus (MRL-Faslpr IL-10+/- and MRL-Faslpr IL-10+/+ mice, respectively). Importantly, Yin et al teach that MRL-Faslpr IL-10-/- mice developed severe lupus, with earlier appearance of skin lesions, increased lymphadenopathy, more severe glomerulonephritis, and higher mortality than their IL-10-intact littermate controls. The increased severity of lupus in MRL-Faslpr IL-10-/- mice was closely associated with enhanced IFN- production by both CD4 and CD8 cells and increased serum concentration of IgG2a anti-dsDNA autoantibodies. The results provide evidence that IL-10 can down-modulate murine lupus through inhibition of pathogenic Th1 cytokine responses. Modulation of the level of IL-10 may be of potential therapeutic benefit for human lupus (abstract). Yin et al demonstrate that IL-10 plays a critical role in down-modulating murine lupus through inhibition of IFN- production. These results have significant implications for the pathogenesis and treatment of human SLE (page 2155, last ¶).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to target SLE subject having an IL-10 plasma concentration lower than about 2 pg/ml taught by Yin et al with the anifrolumab which reduced disease activity across multiple clinical end points in the patients with moderate- to-severe SLE taught by Furie et al because low levels of IL-10 are associated with active SLE as taught by Yin et al.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
7. Claims 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over Furie et al. (Arthritis Rheumatol. 69(2):376-386, 2017) in view of Yin et al (The Journal of Immunology, 2002, 169: 2148–2155), as applied to claims 11-13, 15, 75-77 and 87-89 above, and further in view of Yao et al (Human Genomics Proteomics 2008, 2009:article 374312).
The teachings of Furie et al and Yin et al have been discussed, supra.
The reference teachings differ from the claimed invention only in the recitation that the elevated IFNGS comprises at least about four-fold increase in mRNA of at least four of IGI27, IFI44, IFI44L, IFI6 and RSAD2 in a sample from the subject relative to pooled from a healthy patient in claim 14, wherein the mRNA is increased relative to the mRNA of one or more control genes present in the sample in claim 15, the one or more control genes are chosen from GAPDH in claim 16.
Yao et al selected a core group of IFN-α/β-inducible genes and confirmed the microarray results using TaqMan QRT-PCR. Furthermore, we used ex vivo stimulation of healthy donor peripheral blood mononuclear cells (PBMCs) with SLE patient serum and subsequent neutralization with antiIFN-α mAb or anti-IFN-α receptor (IFNAR) mAb to evaluate the contribution of IFN-α to the induction of type I IFNinducible genes in WB of SLE patients. Results were analyzed using BioMark Real-Time PCR Analysis software. Cts above 20 were excluded from the calculation. Delta-delta Cts (ΔΔCt) were calculated using the mean of 4 reference genes (GAPDH, TFRC, β2M, and 18S) and a calibrator sample (see section 2.7). Table 2 show an eleavated IFNGS comprises at least about four-fold increase in mRNA of at least four of IFI27 (log2=4 (i.e., 16 folds), IFI44 (8 folds), IFI44L (~8 folds), IFI6 (8 folds) and RSAD2 (8 folds) in a whole blood (WB) sample from the subject compared to pooled sample from healthy patients (see Fig. 1 and Table 2).
PNG
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334
514
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362
558
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Yao et al teach determined the fold-change differential for a panel of 18 genes between WB of 27 SLE patients and pooled RNA from 24 healthy controls (see section 2.6). Further, Yao et al used samples from SLE patients were run in triplicate using BioMark Real-Time PCR Systems and delta-delta CTs were calculated suing the mean of 4 reference genes (GAPDH, TFRC, β2M, and 18S) and a calibrator sample (see section 2.7).
Those skilled in the art would have had a reason to target SLE patients with IFNGS comprising at least about 4-fold increase in mRNA of at least four of IFI27, IFI44, IFI44L, IFI6 and RSAD2 taught by Yao et al with anifrolumab taught by Furie et al in the treatment of SLE because an increase of at least 4-fold in the IFNGS indicate positive SLE patients as taught by Yao et al. Further, The type I interferon-signature thus provides a potential pharmacodynamic (PD) marker to evaluate inhibition of the molecular target and to help guide dose selection for anti-type I interferon therapies in SLE as taught by Yao et al. Those of skilled in the art would have had a reason to use the housekeeping controls, GAPDH and/or 18S rRNA in determine the elevated IFNGs because GAPDH and 18S RNA are a housekeeping control.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
8. Claims 24-28 are rejected under 35 U.S.C. 103 as being unpatentable over Furie et al. (Arthritis Rheumatol. 69(2):376-386, 2017) in view of Yin et al (The Journal of Immunology, 2002, 169: 2148–2155), as applied to claims 11-13, 15, 75-77 and 87-89 above, and further in view of US 20110281374.
The teachings of Furie et al and Yin et al have been discussed, supra.
The reference teachings differ from the claimed invention only in the recitation that the method comprising determining the IL-10 concentration in a sample from the patient in claims 24-25, measured by immunoassay in claim 26, such as Luminex or Simoa immunoassay in claim 27, wherein the sample is blood, serum or plasma sample in claim 28.
The `374 publication teaches the serum concentration of IL-10 was measured using the luminex assay, carried out according to manufacturer’s instructions [0027].
Those of skilled in the art would have had a reason to measure the IL-10 concentration in the serum of human patient taught by Yin using the Luminex assay taught by the `374 publication because Luminex assay would quantify IL-10 from serum sample.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
9. Claims 78-80 are rejected under 35 U.S.C. 103 as being unpatentable over Furie et al. (Arthritis Rheumatol. 69(2):376-386, 2017) in view of Yin et al (The Journal of Immunology, 2002, 169: 2148–2155), as applied to claims 11-13, 15, 75-77 and 87-89 above and further in view of Bruce et al (Arthritis and Rheumatology, Oct. 2019, 71(10), pp. 4545-4548. Abstract No: 2563).
The teachings of Furie et al and Yin et al have been discussed, supra.
The reference teachings differ from the claimed invention only in the recitation that the treatment comprises administering about 120 mg anifrolumab in claim 78, wherein the anifrolumab is administered subcutaneously in claim 79, administered every week in claim 80.
Bruce et al teach as subcutaneous (SC) administration may offer a greater treatment convenience and accessibility for patients, we evaluated the PK, PD, safety, tolerability, and efficacy of SC anifrolumab, when added to SOC in adults with Type I IFN test-high SLE and active skin disease. Patients (all fulfilling 1997 ACR SLE criteria) were randomized to the following, added to SOC, for up to 52 weeks (followed by an 8-week follow-up period): anifrolumab 150 mg, anifrolumab 300 mg corresponding placebo, all SC Q2W (once every two weeks) (NCT02962960). Anifrolumab exhibited nonlinear PK where trough concentration increases were more than dose-proportional (Figure 1A). At Week 12, the median percentage neutralization of the Type I IFN PD signature was 88.0%, 90.7% and 18.5% in the anifrolumab 150 mg, 300 mg, and placebo groups, respectively; suppression was sustained over the 52-week treatment period (Figure 1B). At Week 12, a ≥75% neutralization of the Type I IFN PD signature was observed in 66.7%, 76.9%, and 11.1% of patients in the anifrolumab 150 mg, 300 mg and placebo groups, respectively. Over 52 weeks, 85.2% (combined anifrolumab) and 77.8% (placebo) of patients experienced ≥1 AE (Table 1). Ten SAEs were reported in 6 patients, all in anifrolumab groups (Table 1). Greater reductions in CLASI activity score were observed at Week 52 in the anifrolumab 150 mg and 300 mg groups, vs. placebo (-10.2 and -13.2, vs. -6.3, respectively) (Figure 2). Bruce concluded that the observed PK/PD profile of SC anifrolumab was consistent with previous studies using IV administration. In addition, SC anifrolumab showed low immunogenicity and an acceptable safety and tolerability profile, similar to previous, larger IV studies in SLE. These findings support further development of SC anifrolumab as a treatment for SLE (see abstract).
Given that PK/PD profile of SC anifrolumab was consistent with previous studies using IV administration, those of skilled in the art would have had a reason to administer the anifrolumab subcutaneously as taught by Bruce et in the SLE treatment method taught by combined Furie et al and Yin et al teachings.
The claimed specific doses of “about 120 mg” “every week” of the antibody are not significantly different from the ranges of doses known in the art. The Bruce demonstrated that the claimed doses are not significantly different from the claimed doses. PK/PD profile of SC anifrolumab was consistent with previous studies using IV administration. Bruce et al shows that SC administration 150 mg and 300 mg every two weeks provides greater reductions in CLASI activity score at 52 week, those skilled in the art would be motivated to determine the optimum SC anifrolumab dose concentrate given every week because concentration is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Further, the determination of the optimal dosage and the duration of treatment is well within the purview of one of ordinary skill in the art at the time the invention was made and lends no patentable import to the claimed invention. It has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454,456,105 USPQ 233; 235 (CCPA 1955). see MPEP § 2144.05 part II.
“It is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456 (CCPA 1995); see also In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003). “Only if the “results of optimizing a variable” are “unexpectedly good” can a patent be obtained for the claimed critical range.” In re Geisler, 116 F.3d 1465, 1469 (Fed. Cir. 1997) (quoting In re Antonie, 559 F.2d 618, 620 (CCPA 1997)). “Discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” In re Boesch, 617 F.2d 272, 276 (CCPA 1980).
The court has also determined that the availability of specific instructions to achieve the claimed subject matter can form the basis for a reasonable expectation of success. In Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1367-68 (Fed. Cir. 2007), a reasonable expectation of success was found where the prior art included several references with directions for narrowing the possible salts previously approved and the result could be verified by routine trial-and-error procedures.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
10. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
11. Claims 11-16, 24-28, 75-80 and 87-89 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 12410254 B2 in view of Yin et al (The Journal of Immunology, 2002, 169: 2148–2155).
US 12060429 B2 has the same assignee, ASTRAZENECA AB and claims 1-3 below are drawn to a method of treating SLE with anifrolumab. The patent claims differ from the claimed invention only in the recitation that the subject has an IL-10 plasma concentration lower than about 2 pg/ml at baseline in claims 11 and 87.
A method of treating type I interferon (IFN)-mediated disease in a subject comprising subcutaneously administering a unit dose comprising 120 mg to 135 mg of a type I interferon (IFN) receptor (IFNAR1) inhibitor, wherein the IFNAR1 inhibitor is anifrolumab and wherein the unit dose is for subcutaneous injection once per week (QW) to the subject in need thereof.
4. The method of claim 3, wherein the disease is systemic lupus erythematosus (SLE).
5. The method of claim 4, wherein the disease is moderate to severe, active autoantibody-positive SLE.
Yin et al of record teach that low levels of IL-10 are associated with active SLE. In particular, Yin et al teach the role of IL-10 in the regulation of murine lupus, IL-10 gene-deficient (IL-10-/-) MRL-Faslpr (MRL-Faslpr IL-10-/-) mice (i.e., lower than about 2 pg/ml) were generated and their disease phenotype was compared with littermates with one or two copies of an intact IL-10 locus (MRL-Faslpr IL-10+/- and MRL-Faslpr IL-10+/+ mice, respectively). Importantly, Yin et al teach that MRL-Faslpr IL-10-/- mice developed severe lupus, with earlier appearance of skin lesions, increased lymphadenopathy, more severe glomerulonephritis, and higher mortality than their IL-10-intact littermate controls. The increased severity of lupus in MRL-Faslpr IL-10-/- mice was closely associated with enhanced IFN- production by both CD4 and CD8 cells and increased serum concentration of IgG2a anti-dsDNA autoantibodies. The results provide evidence that IL-10 can down-modulate murine lupus through inhibition of pathogenic Th1 cytokine responses. Modulation of the level of IL-10 may be of potential therapeutic benefit for human lupus (abstract). Yin et al demonstrate that IL-10 plays a critical role in down-modulating murine lupus through inhibition of IFN- production. These results have significant implications for the pathogenesis and treatment of human SLE (page 2155, last ¶).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to target SLE subject having an IL-10 plasma concentration lower than about 2 pg/ml taught by Yin et al with the anifrolumab which reduced disease activity across multiple clinical end points in the patients with moderate- to-severe SLE taught by Furie et al because low levels of IL-10 are associated with active SLE as taught by Yin et al.
12. No claim is allowed.
13. The art made of record and not relied upon is considered pertinent to applicant's disclosure:
Casey et al (Arthritis&Rheumatology 73(3), Accepted manuscript online Sept. 10, 2020).
Casey et al teach the modulation of Cardiometabolic disease markers by Type I interferon inhibition in systemic lupus erythematosus. In particular, Casey et al teach that subjects comprised patients with moderate-to-severe SLE who were enrolled in phase IIb of the MUSE trial (A Phase II, Randomized Study to Evaluate the Efficacy and Safety of MEDI-546 in Subjects with Systemic Lupus Erythematosus), with healthy individuals as controls. Blood samples were collected from SLE patients (n = 305) and healthy controls (n = 10–20) before the initiation of treatment (baseline) and from SLE patients after they had been treated with 300 mg of anifrolumab (n = 99) or placebo (n = 102). Baseline IFN gene signature test status was determined, and the IFN gene signature (21-gene panel) was monitored over time. Serum proteins were measured by multiplex immunoassay or ultrasensitive Simoa assay. NET complexes, cholesterol efflux capacity (CEC), and glycoprotein acetylation (GlycA) and other lipid parameters were assessed in plasma. The results show that formation of NET complexes and levels of tumor necrosis factor (TNF) and interleukin-10 (IL-10) were correlated with extent of type I IFN pathway activity. NET complexes and IL-10 levels were up-regulated in SLE patients compared to healthy controls (see abstract).
Morand et al. TULIP-2 Trial Investigators. Trial of Anifrolumab in Active Systemic Lupus Erythematosus. N Engl J Med. 2020 Jan 16;382(3):211-221. doi: 10.1056/NEJMoa1912196. Epub 2019 Dec 18. PMID: 31851795.
Furie et al; CD1013 Study Investigators. Anifrolumab, an Anti-Interferon-α Receptor Monoclonal Antibody, in Moderate-to-Severe Systemic Lupus Erythematosus. Arthritis Rheumatol. 2017 Feb;69(2):376-386. doi: 10.1002/art.39962. PMID: 28130918; PMCID: PMC5299497.
Furie RA, Morand EF, Bruce IN, et al. Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial. Lancet Rheumatol 2019; 1(4):e208-e219.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAHER M HADDAD whose telephone number is (571)272-0845. The examiner can normally be reached on Monday-Friday from7:00AM to 4:30PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu, can be reached at telephone number 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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December 9, 2025
/MAHER M HADDAD/ Primary Examiner, Art Unit 1644